Substituted hexahydropyrazino (1,2-a) pyrimidine-4,7-dione derivatives, processes for their preparation and their use as medicaments

ABSTRACT

Substituted hexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives, processes for their preparation and their use as medicaments The invention relates to substituted hexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives and to the physiologically tolerated salts and physiologically functional derivatives thereof. 
 
Compounds of the formula I  
                 
in which the radicals have the stated meanings, and the physiologically tolerated salts thereof and processes for preparing them are described. The compounds are suitable for example as anorectic agents.

Substituted hexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives,processes for their preparation and their use as medicaments

The invention relates to substitutedhexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives and to thephysiologically tolerated salts and physiologically functionalderivatives thereof.

The invention was based on the object of providing compounds which bringabout a weight reduction in mammals and are suitable for the preventionand treatment of obesity.

The invention therefore relates to compounds of the formula I,

wherein

-   A is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, and 12-membered mono-,    bi- or spirobicyclic ring containing one or more heteroatoms    selected from the group of N, O and S, and is optionally substituted    with F, Cl, Br, NO₂, CF₃, OCF₃, CN, (C₁-C₆)-alkyl, aryl,    CON(R11)(R12), N(R13)(R14), OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl,    N(R15)CO(C₁-C₆)-alkyl or COO—(C₁-C₆)-alkyl;    R11, R12, R13, R14, R15 are each independently H, (C₁-C₆)-alkyl or a    heterocycle;-   n is 0 or 1;-   m is 0, 1, 2, 3, 4, 5 or 6;-   R1 is R8, (C₁-C₆)-alkylene-R8, (C₂-C₆)-alkenylene-R9, (SO₂)-R8,    (SO₂)-(C₁-C₆)-alkylene-R8, (SO₂)-(C₂-C₆)-alkenylene-R9, (C═O)-R8,    (C═O)-(C₁-C₆)-alkylene-R8, (C═O)NH-R8, (C═O)-(C₂-C₆)-alkenylene-R9,    (C═O)—NH—(C₁-C₆)-alkylene-R8, (C═O)—NH—(C₂-C₆)-alkenylene-R9,    COO-R8, COO—(C₁-C₆)-alkylene-R8, COO-(C₂-C₆)-alkenylene-R9,    alkynylene-R9 or (C₁-C₄-alkyl)-heterocycle, wherein the alkylene    component of said (C₁-C₆)-alkylene-R8, (C₂-C₆)-alkenylene-R9,    (SO₂)—(C₁-C₆)-alkylene-R8, (SO₂)-(C₂-C₆)-alkenylene-R9,    (C═O)-(C₁-C₆)-alkylene-R8, (C═O)-(C₂-C₆)-alkenylene-R9,    (C═O)—NH—(C₁-C₆)-alkylene-R8, (C═O)—NH—(C₂-C₆)-alkenylene-R9,    COO—(C₁-C₆)-alkylene-R8, COO—(C₂-C₆)-alkenylene-R9 and alkynylene-R9    groups is optionally substituted by F;-   R8, R9 are each independently H, F, Cl, Br, I, OH, CF₃, aryl,    heterocycle or (C₃-C₈)-cycloalkyl, wherein said aryl, heterocycle    and (C₃-C₈)-cycloalkyl groups are optionally mono-, di- or    tri-substituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,    O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, CON(R11)(R12), N(R13)(R14),    SO₂-CH₃, COOH, COO—(C₁-C₆)-alkyl or CONH₂;-   R2 is H, F, Cl, Br, I, OH, CF₃, CN, OCF₃, O—(C₁-C₆)-alkyl,    O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,    (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, aryl,    O—aryl, (C₁-C₈)-alkylene-aryl, O—(C₁-C₈)-alkylene-aryl, S-aryl,    CON(R11)(R12), N(R13)(R14), (C₁-C₆)-alkyl-N(R13)(R14), COOH,    COO—(C₁-C₆)-alkyl, COO—(C₂-C₆)-alkenyl, CO—N((C₁-C₆)-alkyl)₂ or    heterocycle, with the proviso that said heterocycle may not be    bonded via a nitrogen atom;-   R3, R4, R5 are each independently H, F, Cl, Br, I, OH, CF₃, NO₂, CN,    OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,    S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,    O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl,    (C₂-C₆)-alkynyl, aryl, O-aryl (C₁-C₈)-alkylene-aryl,    O—(C₁-C₈)-alkylene-aryl, S-aryl, N((C₁-C₆)-alkyl)₂, SO₂-CH₃, COOH,    COO—(C₁-C₆)-alkyl or CO—N((C₁-C₆)-alkyl)₂;-   R6 is H, F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,    O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,    (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl,    (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl,    N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl or    CO—N((C₁-C₆)-alkyl)₂;    and pharmaceutically acceptable salts thereof.

Preference is given to compounds of the formula I in which the meaningsare

-   A is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, and 12-membered mono-,    bi- or spirobicyclic ring containing one or more heteroatoms    selected from the group of N, O and S, and is optionally substituted    with F, Cl, Br, NO₂, CF₃, OCF₃, CN, (C₁-C₆)-alkyl, aryl,    CON(R11)(R12), N(R13)(R14), OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl,    N(R15)CO(C₁-C₆)-alkyl or COO—(C₁-C₆)-alkyl;

R11, R12, R13, R14, R15 are each independently H, (C₁-C₆)-alkyl or aheterocycle;

-   m is 1;-   n is 0 or 1;-   R1 is R8, (C₁-C₆)-alkylene-R8, (C₂-C₆)-alkenylene-R9, (SO₂)-R8,    (SO₂)-(C₁-C₆)-alkylene-R8, (SO₂)-(C₂-C₆)-alkenylene-R9, (C═O)-R8,    (C═O)-(C₁-C₆)-alkylene-R8, (C═O)NH-R8, (C═O)—(C₂-C₆)-alkenylene-R9,    (C═O)—NH—(C₁-C₆)-alkylene-R8, (C═O)—NH—(C₂-C₆)-alkenylene-R9,    COO-R8, COO—(C₁-C₆)-alkylene-R8, COO—(C₂-C₆)-alkenylene-R9,    alkynylene-R9 or (C₁-C₄-alkyl)-heterocycle;-   R8, R9 are each independently H, F, Cl, Br, I, OH, CF₃, aryl,    heterocycle or (C₃-C₈)-cycloalkyl, wherein said aryl, heterocycle    and (C₃-C₈)-cycloalkyl groups are optionally mono-, di- or    tri-substituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,    O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, CON(R11)(R12), N(R13)(R14),    SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl or CONH₂;-   R2 is H, F, Cl, Br, I, OH, CF₃, CN, OCF₃, O—(C₁-C₆)-alkyl,    O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,    (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, aryl,    O-aryl, (C₁-C₈)-alkylene-aryl, O—(C₁-C₈)-alkylene-aryl, S-aryl,    CON(R11)(R12), N(R13)(R14), (C₁-C₆)-alkyl-N(R13)(R14), COOH,    COO—(C₁-C₆)-alkyl, COO—(C₂-C₆)-alkenyl, CO—N((C₁-C₆)-alkyl)₂ or    heterocycle, with the proviso that said heterocycle may not be    bonded via a nitrogen atom;-   R3, R4, R5 are each independently H, F, Cl, Br, I, OH, CF₃, NO₂, CN,    OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,    S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,    O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl,    (C₂-C₆)-alkynyl, aryl, O-aryl (C₁-C₈)-alkylene-aryl,    O—(C₁-C₈)-alkylene-aryl, S-aryl, N((C₁-C₆)-alkyl)₂, SO₂-CH₃, COOH,    COO—(C₁-C₆)-alkyl or CO—N((C₁-C₆)-alkyl)₂;-   R6 is H, F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,    O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,    (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, aryl,    O-aryl, (C₁-C₈)-alkylene-aryl, O—(C₁-C₈)-alkylene-aryl, S-aryl,    N((C₁-C₆)-alkyl)₂, SO₂-CH₃, COOH, COO—(C₁-C₆)-alkyl or    CO—N((C₁-C₆)-alkyl)₂;    and pharmaceutically acceptable salts thereof

Particular preference is given to compounds of the formula I in whichthe meanings are

-   A is aryl wherein said aryl is optionally substituted by F, Cl, Br,    NO₂, CF₃, OCF₃, CN, (C₁-C₆)-alkyl, aryl, CON(R11)(R12), N(R13)(R14),    OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, N(R15)CO(C₁-C₆)-alkyl or    COO—(C₁-C₆)-alkyl;

R11, R12, R13, R14, R15 are each independently H or (C₁-C₆)-alkyl;

-   m is 1;-   R1 is (C₁-C₆)-alkylene-R8 or (C₂-C₆)-alkenylene-R9;-   R8, R9 are each independently H, F, Cl, Br, I, OH, CF₃, aryl,    heterocycle or (C₃-C₈)-cycloalkyl, wherein said aryl, heterocycle    and (C₃-C₈)-cycloalkyl groups are optionally mono-, di-, or    tri-substituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,    O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, CON(R11)(R12), N(R13)(R14),    SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl or CONH₂;-   R2 is H, F, Cl, Br, I, OH, CF₃, CN, OCF₃, O—(C₁-C₆)-alkyl,    (C₁-C₆)-alkyl, N(R13)(R14), (C₁-C₆)-alkyl-N(R13)(R14) or    COO—(C₂-C₆)-alkenyl,-   R3 is H-   R4, R5 are each independently H, F, Cl, Br, OH, CF₃, OCF₃,    O—(C₁-C₆)-alkyl or (C₁-C₆)-alkyl;-   R6 is H;    and pharmaceutically acceptable salts thereof

Very particular preference is given to compounds of the formula I inwhich the meanings are

-   A is aryl wherein said aryl is optionally substituted by F, Cl, Br,    NO₂, CF₃, OCF₃, CN, (C₁-C₆)-alkyl, aryl, CON(R11)(R12), N(R13)(R14),    OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, N(R15)CO(C₁-C₆)-alkyl or    COO—(C₁-C₆)-alkyl;-   R11, R12, R13, R14, R15 are each independently H or (C₁-C₆)-alkyl;-   m is 1;-   n is 0 or 1;-   R1 is (C₁-C₆)-alkyl or (C₂-C₆)-alkenyl;-   R2 is H, OH, (C₁-C₆)-alkyl, COO—(C₂-C₆)-alkenyl or    (C₁-C₆)-alkyl-N(R13)(R14);-   R3 is H-   R4 is F, Cl, Br, OH, CF₃, OCF₃, O—(C₁-C₆)-alkyl or (C₁-C₆)-alkyl;-   R5 is H, F, Cl, Br, OH, CF₃, OCF₃, O—(C₁-C₆)-alkyl or (C₁-C₆)-alkyl;-   R6 is H;    and pharmaceutically acceptable salts thereof.

If radicals or substituents may occur more than once in the compounds ofthe formula I, such as, for example, CON(R11)(R12), they may all have,independently of one another, the stated meanings and be identical ordifferent.

The invention relates to compounds of the formula I in the form of theirracemates, enantiomer-enriched mixtures and pure enantiomers, and totheir diastereomers and mixtures thereof.

The alkyl, alkenyl and alkynyl radicals in the substituents A, R1, R2,R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, R14, R15 maybe eitherstraight-chain, branched or optionally halogenated. The alkyl radicalsin the substituents A, R1, R2, R3, R4, R5, R6, R8, R9, R, R11, R12, R13,R14, R15 may also be cyclic.

The term “aryl” means a phenyl or naphthyl group.

Heterocycle or heterocyclic radical means ring systems which, apart fromcarbon, also comprise heteroatoms such as, for example, nitrogen, oxygenor sulfur. This definition also includes ring systems in which theheterocycle or the heterocyclic radical is fused to benzene nuclei.

Suitable “heterocyclic rings” or “heterocyclic radicals” are acridinyl,azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl,benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl,4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]-tetrahydrofuran, furyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazoles, pyridoimidazoles,pyridothiazoles, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl,thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xanthenyl.

Pyridyl stands both for 2-, 3- and 4-pyridyl. Thienyl stands both for 2-and 3-thienyl. Furyl stands both for 2- and 3-furyl.

The corresponding N-oxides of these compounds are also included, that isto say, for example, 1-oxy-2-, 3- or 4-pyridyl.

Also included are derivatives of these heterocycles which arebenzo-fused one or more times.

The heterocyclic rings or heterocyclic radicals may be substituted oneor more times by suitable groups such as, for example, F, Cl, Br, I,CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₆)alkyl,CON[(C₁-C₆)alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,O—(C₁-C₆)-alkyl, where one or more than one, or all hydrogen(s) in thealkyl radicals may be replaced by fluorine;

PO₃H₂, SO₃H, SO₂-NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂,S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl,SO—(CH₂)_(n)-phenyl, SO₂-(C₁-C₆)-alkyl, SO₂-(CH₂)_(n)-phenyl, where ncan be 0-6, and the phenyl radical may be substituted up to twice by F,Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂;C(NH)(NH₂), NH₂, NH-(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NH(C₁-C₇)-acyl,phenyl, O—(CH₂)_(n)-phenyl, where n may be 0-6, and where the phenylring may be substituted one to 3 times by F, Cl, Br, I, OH, CF₃, NO₂,CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl,N((C₁-C₆)-alkyl)₂, SO₂-CH₃, COOH, COO—(C₁-C₆)-alkyl, CONH₂.

Pharmaceutically acceptable salts are particularly suitable for medicalapplications because their solubility in water is higher than theinitial or basic compounds. These salts must have a pharmaceuticallyacceptable anion or cation. Suitable pharmaceutically acceptable acidaddition salts of the compounds of the invention are salts of inorganicacids such as hydrochloric acid, hydrobromic acid, phosphoric,metaphosphoric, nitric, sulfamic and sulfuric acids, and organic acidssuch as, for example, acetic acid, benzenesulfonic, benzoic, citric,ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, succinic,p-toluenesulfonic, tartaric and trifluoroacetic acids. The chloride saltis particularly preferably used for medical purposes. Suitablepharmaceutically acceptable basic salts are ammonium salts, alkali metalsalts (such as sodium and potassium salts) and alkaline earth metalsalts (such as magnesium and calcium salts).

Salts with a pharmaceutically unacceptable anion likewise fall withinthe scope of the invention as useful intermediates for preparing orpurifying pharmaceutically acceptable salts and/or for use innontherapeutic, for example in vitro, applications.

As used herein, the following definitions apply:

“Patient” means a warm blooded animal, such as for example rat, mice,dogs, cats, guinea pigs, and primates such as humans.

“Treat” or “treating” means to alleviate symptoms, eliminate thecausation of the symptoms either on a temporary or permanent basis, orto prevent or slow the appearance of symptoms of the named disorder orcondition.

“Therapeutically effective amount” means a quantity of the compoundwhich is effective in treating the named disorder or condition.

“Pharmaceutically acceptable carrier” is a non-toxic solvent,dispersant, excipient, adjuvant or other material which is mixed withthe active ingredient in order to permit the formation of apharmaceutical composition, i.e., a dosage form capable ofadministration to the patient. One example of such a carrier is apharmaceutically acceptable oil typically used for parenteraladministration.

The term “physiologically functional derivative” used herein refers toany physiologically tolerated derivative of a compound according to theinvention of the formula I, for example an ester, which is able onadministration to a mammal such as, for example, a human to form(directly or indirectly) a compound of the formula I or an activemetabolite thereof.

The physiologically functional derivatives also include prodrugs of thecompounds according to the invention. Such prodrugs can be metabolizedin vivo to a compound according to the invention. These prodrugs maythemselves be active or not.

The compounds according to the invention may also exist in variouspolymorphous forms, for example as amorphous and crystallinepolymorphous forms. All polymorphous forms of the compounds according tothe invention lie within the scope of the invention and are a furtheraspect of the invention.

All references hereinafter to “compound(s) of formula (I)” refer tocompound(s) of the formula (I) as described above, and the salts,solvates and physiologically functional derivatives thereof as describedherein.

The amount of a compound of formula (I) which is necessary to achievethe desired biological effect depends on a number of factors, forexample the specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. In general,the daily dose is in the range from 0.3 mg to 100 mg (typically from 3mg to 50 mg) per day and per kilogram of body weight, for example 3-10mg/kg/day. An intravenous dose may be, for example, in the range from0.3 mg to 1.0 mg/kg, which can most suitably be administered as infusionof from 10 ng to 100 ng per kilogram and per minute. Suitable infusionsolutions for these purposes may contain, for example, from 0.1 ng to 10mg, typically from 1 ng to 10 mg, per milliliter. Single doses maycontain, for example, from 1 mg to 10 g of the active ingredient. It isthus possible for ampoules for injections to contain, for example, from1 mg to 100 mg, and single-dose formulations which can be administeredorally, such as, for example, tablets or capsules, to contain, forexample, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the caseof pharmaceutically acceptable salts, the aforementioned weight data arebased on the weight of the salt—underlying free compound. For theprophylaxis or therapy of the abovementioned conditions, the compoundsof formula (I) can be used as the compound itself, but they arepreferably in the form of a pharmaceutical composition with anacceptable carrier. The carrier must, of course, be acceptable in thesense that it is compatible with the other ingredients of thecomposition and is not hazardous for the patient's health. The carriermay be a solid or a liquid or both and is preferably formulated with thecompound as single dose, for example as tablet which may contain from0.05% to 95% by weight of the active ingredient. Furtherpharmaceutically active substances may likewise be present, includingother compounds of formula (I). The pharmaceutical compositionsaccording to the invention can be produced by one of the knownpharmaceutical methods which essentially consist of mixing theingredients with pharmacologically acceptable carriers and/orexcipients.

Pharmaceutical compositions according to the invention are thosesuitable for oral, rectal, topical, peroral (for example sublingual) andparenteral (for example subcutaneous, intramuscular, intradermal orintravenous) administration although the most suitable mode ofadministration in each individual case depends on the nature andseverity of the condition to be treated and on the nature of thecompound of formula (I) used in each case. Coated formulations andcoated slow-release formulations also lie within the scope of theinvention. Formulations resistant to acid and gastric fluid arepreferred. Suitable coatings resistant to gastric fluid comprisecellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration may be in theform of separate units such as, for example, capsules, cachets, suckabletablets or tablets, each of which contain a defined amount of thecompound of formula (I); as powders or granules; as solution orsuspension in an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. These compositions may, as already mentioned, beprepared by any suitable pharmaceutical method which includes a step inwhich the active ingredient and the carrier (which may consist of one ormore additional ingredients) are brought into contact. In general, thecompositions are produced by uniform and homogeneous mixing of theactive ingredient with a liquid and/or finely divided solid carrier,after which the product is shaped if necessary. Thus, for example, atablet can be produced by compressing or molding a powder or granules ofthe compound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form, such as, for example, a powder or granules, whereappropriate mixed with a binder, lubricant, inert diluent and/or a(plurality of) surface-active/dispersing agent(s) in a suitable machine.Molded tablets can be produced by molding the compound which is inpowder form and is moistened with an inert liquid diluent in a suitablemachine.

Pharmaceutical compositions suitable for peroral (sublingual)administration comprise suckable tablets which contain a compound offormula (I) with a flavoring, normally sucrose and gum arabic ortragacanth, and pastilles which comprise the compound in an inert basesuch as gelatin and glycerol or sucrose and gum arabic.

Suitable pharmaceutical compositions for parenteral administrationcomprise preferably sterile aqueous preparations of a compound offormula (I), which are preferably isotonic with the blood of theintended recipient. These preparations are preferably administeredintravenously, although administration may also take place bysubcutaneous, intramuscular or intradermal injection. These preparationscan preferably be produced by mixing the compound with water and makingthe resulting solution sterile and isotonic with blood. Injectablecompositions according to the invention generally contain from 0.1 to 5%by weight of the active compound.

Suitable pharmaceutical compositions for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of formula (I) with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

Suitable pharmaceutical compositions for topical application to the skinare preferably in the form of ointment, cream, lotion, paste, spray,aerosol or oil. Carriers which can be used are petrolatum, lanolin,polyethylene glycols, alcohols and combinations of two or more of thesesubstances. The active ingredient is generally present in aconcentration of from 0.1 to 15% by weight of the composition, forexample from 0.5 to 2%.

Transdermal administration is also possible. Suitable pharmaceuticalcompositions for transdermal uses can be in the form of single plasterswhich are suitable for long-term close contact with the patient'sepidermis. Such plasters suitably contain the active ingredient in anoptionally buffered aqueous solution, dissolved and/or dispersed in anadhesive or dispersed in a polymer. A suitable active ingredientconcentration is about 1% to 35%, preferably about 3% to 15%. As aspecial possibility, the active ingredient can be released as described,for example, in Pharmaceutical Research, 2(6): 318 (1986) byelectrotransport or iontophoresis.

The compounds of the formula I are distinguished by beneficial effectson lipid metabolism, and they are particularly suitable for weightreduction and for maintaining a reduced weight after weight reductionhas taken place in mammals and as anorectic agents. The compounds aredistinguished by their low toxicity and their few side effects. Thecompounds can be employed alone or in combination with otherweight-reducing or anorectic active ingredients. Further anorecticactive ingredients of this type are mentioned, for example, in the RoteListe, chapter 01 under weight-reducing agents/appetite suppressants,and may also include active ingredients which increase the energyturnover of the organism and thus lead to weight reduction or else thosewhich influence the general metabolism of the organism in such a waythat an increased calorie intake does not lead to an enlargement of thefat depots and a normal calorie intake leads to a reduction of the fatdepots of the organism. The compounds are suitable for the prophylaxisand, in particular, for the treatment of excessive weight or obesity.The compounds are further suitable for the prophylaxis and, inparticular, for the treatment of type II diabetes, of arteriosclerosisand for normalizing lipid metabolism and for the treatment of high bloodpressure. The compounds act as melanocortin receptor agonists and arealso suitable for the treatment of disturbances of well being and otherpsychiatric indications such as, for example, depressions, anxietystates, anxiety neuroses, schizophrenia and for the treatment ofdisorders associated with the circadian rhythm and for the treatment ofdrug abuse.

They are additionally suitable for the treatment of cancer, arthritis,sleep disorders, sleep apnoea, female and male sexual disorders,inflammations, acne, pigmentation of the skin, of metabolic syndrome,disorders of steroid metabolism, skin diseases, psoriasis, mycoses,neurodegenerative diseases and Alzheimer's disease.

In a further aspect of the invention, the compounds of the formula I canbe administered in combination with one or more other pharmacologicallyactive substances which are selected, for example, from antidiabetics,antiobesity agents, active ingredients which lower blood pressure,lipid-lowering agents and active ingredients for the treatment and/orprevention of complications caused by diabetes or associated withdiabetes.

Suitable antidiabetics include insulins, amylin, derivatives of GLP-1and GLP-2 such as, for example, those disclosed in WO 98/08871 of NovoNordisk A/S, and orally active hypoglycemic active ingredients.

The orally active hypoglycemic active ingredients preferably comprisesulfonylureas, biguanides, meglitinides, oxadiazolidinediones,thiazolidinediones, glucosidase inhibitors, glucagon receptorantagonists, GLP-1 agonists, potassium channel openers such as, forexample, those disclosed in WO 97/26265 and WO 99/03861 of Novo NordiskA/S, insulin sensitizers, activators of insulin receptor kinase,inhibitors of liver enzymes involved in the stimulation ofgluconeogenesis and/or glycogenolysis, for example inhibitors ofglycogen phosphorylase, modulators of glucose uptake and glucoseexcretion, compounds which alter lipid metabolism, such asantihyperlipidemic active ingredients and antilipidemic activeingredients, for example HMGCoA reductase inhibitors, inhibitors ofcholesterol transport/of cholesterol uptake, inhibitors of bile acidreabsorption or inhibitors of the microsomal triglyceride transferprotein (MTP), compounds which reduce food intake, PPAR and RXR agonistsand active ingredients which act on the ATP-dependent potassium channelof the beta cells.

In one embodiment of the invention, the present compounds areadministered in combination with insulin.

In a further embodiment, the present compounds are administered incombination with a sulfonylurea such as, for example, tolbutamide,glibenclamide, glimepiride, glipizide, gliquidone, glisoxepide,glibomuride or gliclazide.

In another embodiment, the present compounds are administered incombination with a biguanide such as, for example, metformin.

In yet another embodiment, the present compounds are administered incombination with a meglitinide such as, for example, repaglinide.

In yet a further embodiment, the present compounds are administered incombination with a thiazolidinedione such as, for example, troglitazone,ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed inWO 97/41097 of Dr. Reddy's Research Foundation, in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In a further embodiment, the present compounds are administered incombination with an α-glucosidase inhibitor such as, for example,miglitol or acarbose.

In another embodiment, the present compounds are administered incombination with an active ingredient which acts on the ATP-dependentpotassium channel of the beta cells, such as, for example, tolbutamide,glibenclamide, glimepiride, glipizide, gliclazide or repaglinide.

In yet another embodiment, the present compounds are administered incombination with an antihyperlipidemic active ingredient or anantilipidemic active ingredient such as, for example, cholestyramine,colestipol, clofibrate, fenofibrate, gemfibrozil, lovastatin,pravastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin,probucol, ezetimibe or dextrothyroxine.

In a further embodiment, the present compounds are administered incombination with more than one of the aforementioned compounds, e.g. incombination with a sulfonylurea and metformin, a sulfonylurea andacarbose, repaglinide and metformin, insulin and a sulfonylurea, insulinand metformin, insulin and troglitazone, insulin and lovastatin, etc.

The compounds of the invention may additionally be administered incombination with one or more antiobesity agents or appetite-regulatingactive ingredients.

Active ingredients of these types may be selected from the groupconsisting of CART agonists, NPY antagonists, MCH antagonists, orexinantagonists, H3 antagonists, TNF agonists, CRF agonists, CRF BPantagonists, urocortin agonists, β3 agonists, MSH(melanocyte-stimulating hormone) agonists, CCK agonists,serotonin-reuptake inhibitors, mixed serotonin- andnoradrenaline-reuptake inhibitors, 5HT modulators, MAO inhibitors,bombesin agonists, galanin antagonists, growth hormone, growthhormone-releasing compounds, TRH agonists, modulators of uncouplingproteins 2 or 3, leptin agonists, dopamine agonists (bromocriptine,Doprexin), lipase/amylase inhibitors, antagonists of cannabinoidreceptor 1, modulators of acylation-stimulating protein (ASP), PPARmodulators, RXR modulators, hCNTF agonists or TR-β agonists.

In one embodiment of the invention, the antiobesity agent is leptin ormodified leptin.

In another embodiment, the antiobesity agent is dexamphetamine oramphetamine.

In another embodiment, the antiobesity agent is fenfluramine ordexfenfluramine.

In yet another embodiment, the antiobesity agent is sibutramine or themono- and bisdemethylated active metabolites of sibutramine.

In a further embodiment, the antiobesity agent is orlistat.

In another embodiment, the antiobesity agent is mazindol, diethylpropionor phentermine.

The present compounds may additionally be administered in combinationwith one or more antihypertensive active ingredients. Examples ofantihypertensive active ingredients are beta blockers such asalprenolol, atenol, timolol, pindolol, propranolol and metoprolol, ACE(angiotensin converting enzyme) inhibitors such as, for example,benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril andrampril, calcium channel blockers such as nifedipine, felodipine,nicardipine, isradipine, nimodipine, diltiazem and verapamil, and alphablockers such as doxazosin, urapidil, prazosin and terazosin. Referencemay furthermore be made to Remington: The Science and Practice ofPharmacy, 19th edition, Gennaro, editor, Mack Publishing Co., Easton,Pa., 1995.

It will be appreciated that every suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances is tobe regarded as covered by the scope of protection of the presentinvention.

The efficacy of the compounds was tested as follows:

Biological Test Model:

The anorectic effect was tested on female NMRI mice. After withdrawal offood for 24 hours, the test product was administered by gavage. Theanimals were housed singly with free access to drinking water and wereoffered condensed milk 30 minutes after administration of the product.The condensed milk consumption was determined every half hour for 7hours, and the general wellbeing of the animals was observed. Themeasured milk consumption was compared with the vehicle-treated controlanimals. TABLE 1 Anorectic effect measured as the reduction in thecumulative milk consumption of treated compared with control animalsNumber of Number of Reduction in animals/ animals/ the cumulative milkcumulative milk cumulative consumption consumption of milk Oral of thetreated the control consumption dose animals animals as % of the Example[mg/kg] N/[ml] N/[ml] control 2 50 10/4.90 10/5.48 11

It is evident from the table that the compounds of the formula I show agood anorectic effect and are thus very suitable as antiobesity agent.

The examples and preparation methods detailed below serve to illustratethe invention without, however, restricting it.

General Processes

The starting materials used in the synthesis were purchased fromchemical suppliers such as Aldrich, Acros, Sigma, Fluka, Nova Biochem,Advanced Chemtech, Bachem, Lancaster and other companies.

In the synthesis, the functional groups of the amino acid derivativesused were protected by protective groups to prevent side reactionsduring the coupling steps. Examples of suitable protective groups andtheir use are described in The Peptides, supra, 1981 and in Vol. 9,Udenfriend and Meienhofer (Editors) 1987 (included herein by reference).

General methods of solid-phase synthesis were used to prepare thecompounds of the invention. Methods of this type are described forexample by Steward and Young in Solid Phase Peptide Synthesis (Freeman &Co., San Francisco 1969) (included herein by reference).

Unless indicated otherwise, the compounds were synthesized usingTentaGel HL12019 Resin (Rapp Polymere, Tübingen). This commerciallyavailable polymer contains a bromoacetal linker. This type of couplingcan be incorporated in all types of hydroxy-tentagel by the processdescribed by Vojkovsky, T. et al., J. Org. Chem. 1998, 63, 3162-3163,and Patek, M., Contribution to Combinatorial Chemistry 2000, London,11.-14.7. 2000 (included herein by reference).

In the first synthesis step (see scheme 1 for general synthetic scheme),amine was used in DMSO to replace bromine in the bromoacetal link at anelevated temperature. Fmoc-protected amino acid was coupled onto thesecondary amine produced thereby on the polymer. The coupling waseffected by means of DIC/HOAt or HATU/DIEA, usually in DMF. The couplingwas carried out at room temperature (RT) for 16 hours or at 55° C. for4-5 hours. Protection by the Fmoc group was eliminated by using 50%piperidine in DMF (5+15 minutes). The substitution can be determined bymeasuring the amount of liberated

Fmoc from the absorbance of the solution at 302 nm after elimination ofthe protection, the volume of the washing liquid and the weight of thepolymer employed in the synthesis in accordance with the description inKrchnak, V. et al., Collect. Czech. Chem. Commun. 53 (1988) 2542(incorporated herein by reference).

The free amino group of the structure bound to the solid phase was thencoupled to Fmoc-beta-alanine (or Fmoc-alpha-amino acid or substitutedbeta-amino acid). The coupling was effected withN,N′-diisopropylcarbodiimide (DIC) in the presence of HOBt, usually inDMF. The completeness of the coupling was monitored by the ninhydrintest.

A protection by the Fmoc group was eliminated with 50% piperidine in DMFfor 5+15 minutes. The amount of liberated Fmoc was measured from theabsorbance of the solution at 302 nm after elimination of theprotection, the volume of the washing liquid and the weight of thepolymer employed in the synthesis. The free amino groups of thestructure bound to the solid phase was then sulfonylated with up to 2equivalents of a suitable sulfonyl chloride/DIEA in DCM or acetonitrile.The completeness of the sulfonylation was monitored by the ninhydrintest.

After completion of the assembly of the precursor of the linear compoundon the polymer, the solid phase was washed successively with DMF and DCMor THF and dried in vacuo.

The desired compound was subjected to cyclative cleavage off with formicacid at room temperature for 18-24 hours, at 50° C. for 6 hours or by acombination of the two conditions. The polymer was filtered off andwashed with DCM or formic acid. The washing liquid was introduced intothe formic acid solution. The solution was evaporated. The residue wasdissolved in a mixture of water and acetonitrile and freeze dried.

The dried compound was purified with HPLC with a suitable gradient of0.1% TFA in water and acetonitrile (ACN). After collection of the peakcontaining the desired synthetic product, the solution of the compoundwas freeze dried. To confirm that the correct compound had beensynthesized, the compound was subjected to a qualitative determinationwith electrospray mass spectrum (LC/MS) and/or an NMR analysis.

For HPLC analysis a sample of the compound was analyzed with the BeckmanHPLC system (consisting of the solvent supply system 126, theprogrammable detector module 166 and the autosampler 507e and controlledby data station with Gold Nouveau sofware) using a YMC ODS-AM 4.6×250 mmcolumn (S-5 (5 μm), YMC, Inc. Wilmington, N.C., USA) at 230 nm. Withthis setting, a flow rate of 1 ml/min was used and a gradient ofwater/0.1% TFA buffer and ACN (HPL quality) was used as eluent.

The compounds can also be prepared in solution in analogy to thedescribed synthesis on the resin. (Scheme 2). In place of thefunctionalized resin, in the first stage 2-bromo-1,1-diethoxyethane isreacted with a primary amine.

The resulting product is reacted with the amino acid in analogy to thesolid-phase synthesis. The allyloxycarbonyl protective group (Aloc) canbe used in place of FMOC as amino-protective group for the amino acid,and is introduced (Aloc-Cl, triethylamine) and eliminated (Pd(PPh₃)₄,dimethylbarbituric acid) by methods known from the literature.

The amino carboxylic acid with the radical R4 is reacted with thesulfonyl chloride in the presence of triethylamine. The free carboxylicacid is coupled by the carbodiimide method (EDC, HOBt) to the free aminewhich has been obtained by elimination of the Aloc group.

The acidic cyclization of the linear precursor obtained in this way andsubsequent further functionalization proceeds in analogy to the abovedescription.

The product was purified by developing a sample of the freeze-driedcrude substance in a mixture of 0.1% strength aqueous TFA with 10-50%acetonitrile or in acetic acid. The solution of the compound was usuallyfiltered through a syringe connected to an ACRODISC 13 CR PTFE 0.45 μmfilter (Gelman Sciences; Ann Arbor, Mich., USA). An appropriate volumeof the filtered solution of the compound was injected into asemipreparative C 18 column (YMC ODS-AM, S-5 (5 μm), 20×150 mm, YMC,Inc., Wilmington, N.C., USA). The flow rate of the gradient ofwater/0.1% TFA buffer and ACN (HPL quality) as eluent was maintained bymeans of the Beckman SYSTEM GOLD HPLC (System Gold, programmable solventmodule 126 and programmable detector module 166, controlled by SYSTEMGOLD software). Elution of the compound was monitored by UV detection at230 or 280 nm. After identification of the peak of the compound to besynthesized by LC/MS, the compound was collected, freeze dried andsubjected to biological testing.

After purification, compounds with basic groups were obtained astrifluoroacetates. Hydrochlorides of these compounds can easily beprepared by treating the trifluoroacetate of the compound with an excessof HCl/dioxane. After evaporation of the solvents, the hydrochloride ofthe compound was precipitated with diethyl ether and isolated byfiltration.

LC/MS was carried out with PE Sciex API 150EX and Sciex MassChromsoftware, equipped with a Gilson 215 liquid handler, two ShimadzuLC-10AD liquid modules, a Shimadzu SPD-10A detector,a Keystone BetasilC-18 column (2×30 mm, 3 μm, flow rate of the acetonitrile/water/0.1% TFAgradient 0.7 ml/min) in ES+ mode. For the NMR analysis, the samples weremeasured in DMSO-d₆ (Aldrich) with a Bruker Avance DPX 300.

Abbreviations

Unless indicated otherwise, the abbreviations in the examples below havethe following meaning:

-   ACN=Acetonitrile-   Aloc=Allyloxycarbonyl-   DIC=Diisopropylcarbodiimide-   EDC=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide-   FMOC=9-Fluorenylmethyloxycarbonyl-   DCE=1,2-Dichloroethane-   DIEA=Diisopropylethylamine-   NaBH₃CN=Sodium cyanoborohydride-   DMAP=N,N-Dimethylaminopyridine-   DMF=N,N-Dimethylformamide-   THF=Tetrahydrofuran-   DIC=Diisopropylcarbodiimide-   DMSO=Dimethyl sulfoxide-   DCM=Dichloromethane (also referred to as methylene chloride)-   HOBt=1-Hydroxybenzotriazole-   HOAt=1-Hydroxy-7-azabenzotriazole-   HATU=Dimethylamino([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylenedimethyl-ammonium    hexafluorophosphate-   HOAc=Acetic acid-   Et₃N=Triethylamine-   HCl=Hydrochloric acid-   HBr=Hydrobromic acid-   HPLC=High performance liquid chromatography

The citation of any reference herein should not be construed as anadmission that such reference is available as “Prior Art” to the instantapplication.

Various publications are cited herein, the disclosures of which areincorporated by reference in their entireties.

The following examples serve to explain the invention in more detail.The present invention is not to be limited in scope by the specificembodiments describe herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the claims.

EXAMPLE 16-(4-Chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

0.5 g of TentaGel HL12019 (bromoacetal linker, S=0.5 mmol/g, RappPolymere, Tübingen) was washed with DMSO. 20 equivalents of 2Misopropylamine solution (reagent 1) in DMSO were added, and the mixturewas kept in a closed vessel at 60° C. for 15 hours. The polymer waswashed 7 times with DMF.

Fmoc-4-chlorophenylalanine (reagent 2) (3 equivalents) was coupled tothe secondary amine on the polymer with HOAt (3 equivalents) and DIC (3equivalents) in DMF. The final concentration was 0.2-0.3M. The reactionmixture was left to stand at room temperature overnight. The polymer waswashed 6 times with DMF. The Fmoc protective group was eliminated with50% piperidine in DMF (5+15 minutes). Fmoc-beta-alanine (3 equivalents)was then coupled on with HOBt (3 equivalents) and DIC (3 equivalents) inDMF (final concentration: 0.2M) over a period of at least 4 hours. TheFmoc protective group was eliminated with 50% piperidine in DMF (5+15minutes). The polymer was washed 5 times with DMF and 4 times with DCMand mixed with a solution of 1.5 equivalents of2,4-dichlorobenzenesulfonyl chloride (reagent 3) and 3 equivalents ofDIEA in acetonitrile (final concentration: 0.1-0.15M) and reacted atroom temperature for 5 hours. It was then washed 5 times with DMF and 5times with DCM and dried in vacuo.

For the cyclative cleavage off, the dry polymer was mixed with 10 ml offormic acid and shaken at room temperature for 16 hours. The polymer wasfiltered off and washed with DCM. The combined filtrates were evaporatedin vacuo. The crude substance was dissolved in a mixture of acetonitrileand water and freeze dried. The pure title compound was removed afterpurification by HPLC. The system and processes described under “Generalprocesses” were used in this case. MW=543.06 (calculated, monoisotopic);measured value (M+H)⁺: 544.3.

EXAMPLE 26-(4-Chlorobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

0.3 g of TentaGel HL12019 (bromoacetal linker, S=0.5 mmol/g, RappPolymere, Tübingen) was washed with DMSO. 20 equivalents of 2Misopropylamine solution (reagent 1) in DMSO were added, and the mixturewas kept in a closed vessel at 60° C. for 15 hours. The polymer waswashed 7 times with DMF. Fmoc-4-chlorophenylalanine (reagent 2) (3equivalents) was coupled to the secondary amine on the polymer with HATU(3 equivalents) and DIEA (9 equivalents) in DMF. The final concentrationwas 0.2-0.3M. The reaction mixture was left at 55° C. for 4 hours. Thepolymer was washed 6 times with DMF. The Fmoc protective group waseliminated with 50% piperidine in DMF (5+15 minutes).

Fmoc-beta-alanine (3 equivalents) was then coupled on with HOBt (3equivalents) and DIC (3 equivalents) in DMF (final concentration: about0.2M) over a period of at least 4 hours. The Fmoc protective group waseliminated with 50% piperidine in DMF (5+15 minutes).

The polymer was washed 5 times with DMF and 4 times with DCM and mixedwith a solution of 1.5 equivalents of 2-methoxy-4-chlorobenzenesulfonylchloride (reagent 3) and 3 equivalents of DIEA in acetonitrile (finalconcentration: 0.1-0.15M) and reacted at room temperature for 5 hours.It was then washed 5 times with DMF and 5 times with THF and dried invacuo.

For the cyclative cleavage off, the dry polymer was mixed with 10 ml offormic acid and shaken at room temperature for 16 hours. The polymer wasfiltered off and washed with DCM. The combined filtrates were evaporatedin vacuo. The crude substance was dissolved in a mixture of acetonitrileand water and freeze dried. The pure title compound was removed afterpurification by HPLC. The system and processes described under “Generalprocesses” were used in this case. MW=539.10 (calculated, monoisotopic);measured value (M+H)⁺: 540.3.

EXAMPLE 36-Benzyl-1-(5-chloro-2-methoxybenzenesulfonyl)-8-isopropylhexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

0.3 g of TentaGel HL12019 (bromoacetal linker, S=0.5 mmol/g, RappPolymere, Tübingen) was washed with DMSO. 20 equivalents of 2Misopropylamine solution in DMSO were added, and the mixture was kept ina closed vessel at 60° C. for 15 hours. The polymer was washed 7 timeswith DMF.

Fmoc-4-phenylalanine (3 equivalents) was coupled to the secondary amineon the polymer with HATU (3 equivalents) and DIEA (9 equivalents) inDMF. The final concentration was 0.2-0.3M. The reaction mixture was leftat 55° C. for 4 hours. The polymer was washed 6 times with DMF. The Fmocprotective group was eliminated with 50% piperidine in DMF (5+15minutes).

Fmoc-beta-alanine (3 equivalents) was then coupled on with HOBt (3equivalents) and DIC (3 equivalents) in DMF (final concentration: about0.2M) over a period of at least 4 hours. The Fmoc protective group waseliminated with 50% piperidine in DMF (5+15 minutes).

The polymer was washed 5 times with DMF and 4 times with DCM and mixedwith a solution of 1.5 equivalents of 2-methoxy-4-chlorobenzenesulfonylchloride and 3 equivalents of DIEA in acetonitrile (final concentration:0.1-0.15M) and reacted at room temperature for 5 hours. It was thenwashed 5 times with DMF and 5 times with THF and dried in vacuo.

For the cyclative cleavage off, the dry polymer was mixed with 10 ml offormic acid and shaken at room temperature for 16 hours. The polymer wasfiltered off and washed with DCM. The combined filtrates were evaporatedin vacuo. The crude substance was dissolved in a mixture of acetonitrileand water and freeze dried. The pure title compound was removed afterpurification by HPLC. The system and processes described under “Generalprocesses” were used in this case. MW=505.14 (calculated, monoisotopic);measured value (M+H)⁺: 506.3.

EXAMPLE 41-(5-Chloro-2-methoxybenzenesulfonyl)-6-(3,4-Dichlorobenzyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

0.3 g of TentaGel HL12019 (bromoacetal linker, S=0.5 mmol/g, RappPolymere, Tübingen) was washed with DMSO. 20 equivalents of 2Misopropylamine solution in DMSO were added, and the mixture was kept ina closed vessel at 60° C. for 15 hours. The polymer was washed 7 timeswith DMF.

Fmoc-3,4-dichlorophenylalanine (3 equivalents) was coupled to thesecondary amine on the polymer with HATU (3 equivalents) and DIEA (9equivalents) in DMF. The final concentration was 0.2-0.3M. The reactionmixture was left at 55° C. for 4 hours. The polymer was washed 6 timeswith DMF. The Fmoc protective group was eliminated with 50% piperidinein DMF (5+15 minutes).

Fmoc-beta-alanine (3 equivalents) was then coupled on with HOBt (3equivalents) and DIC (3 equivalents) in DMF (final concentration: about0.2M) over a period of at least 4 hours. The Fmoc protective group waseliminated with 50% piperidine in DMF (5+15 minutes).

The polymer was washed 5 times with DMF and 4 times with DCM and mixedwith a solution of 1.5 equivalents of 2-methoxy-4-chlorobenzenesulfonylchloride and 3 equivalents of DIEA in acetonitrile (final concentration:0. 1-0.15M) and reacted at room temperature for 5 hours. It was thenwashed 5 times with DMF and 5 times with THF and dried in vacuo.

For the cyclative cleavage off, the dry polymer was mixed with 10 ml offormic acid and shaken at room temperature for 16 hours. The polymer wasfiltered off and washed with DCM. The combined filtrates were evaporatedin vacuo. The crude substance was dissolved in a mixture of acetonitrileand water and freeze dried. The pure title compound was removed afterpurification by HPLC. The system and processes described under “Generalprocesses” were used in this case. MW=573.07 (calculated, monoisotopic);measured value (M+H)⁺: 574.3.

EXAMPLE 58-Allyl-1-(naphthalene-2-sulfonyl)-6-(4-nitrobenzyl)hexahydropyrazino[1,2-a]-pyrimidine-4,7-dione

Structure:

0.3 g of TentaGel HL12019 (bromoacetal linker, S=0.5 mmol/g, RappPolymere, Tübingen) was washed with DMSO. 20 equivalents of 2Mallylamine solution in DMSO were added, and the mixture was kept in aclosed vessel at 60° C. for 15 hours. The polymer was washed 7 timeswith DMF.

Fmoc-4-nitrophenylalanine (3 equivalents) was coupled to the secondaryamine on the polymer with HATU (3 equivalents) and DIEA (9 equivalents)in DMF. The final concentration was 0.2-0.3M. The reaction mixture wasleft at 55° C. for 4 hours. The polymer was washed 6 times with DMF. TheFmoc protective group was eliminated with 50% piperidine in DMF (5+15minutes).

Fmoc-beta-alanine (3 equivalents) was then coupled on with HOBt (3equivalents) and DIC (3 equivalents) in DMF (final concentration: about0.2M) over a period of at least 4 hours. The Fmoc protective group waseliminated with 50% piperidine in DMF (5+15 minutes).

The polymer was washed 5 times with DMF and 4 times with DCM and mixedwith a solution of 1.5 equivalents of 2-naphthylsulfonyl chloride and 3equivalents of DIEA in acetonitrile (final concentration: 0.1-0.15M) andreacted at room temperature for 5 hours. It was then washed 5 times withDMF and 5 times with THF and dried in vacuo. For the cyclative cleavageoff, the dry polymer was mixed with 10 ml of formic acid and shaken atroom temperature for 16 hours. The polymer was filtered off and washedwith DCM. The combined filtrates were evaporated in vacuo. The crudesubstance was dissolved in a mixture of acetonitrile and water andfreeze dried. The pure title compound was removed after purification byHPLC. The system and processes described under “General processes” wereused in this case. MW=534.16 (calculated, monoisotopic); measured value(M+H)⁺: 535.3.

EXAMPLE 66-(4-Chlorobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-3-Hydroxy-8-Isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

0.5 g of TentaGel HL12019 (bromoacetal linker, S=0.5 mmol/g, RappPolymere, Tubingen) was washed with DMSO. 20 equivalents of 2Misopropylamine solution in DMSO were added, and the mixture was kept ina closed vessel at 60° C. for 15 hours. The polymer was washed 7 timeswith DMF.

Fmoc-4-chlorophenylalanine (3 equivalents) was coupled to the secondaryamine on the polymer with HOAt (3 equivalents) and DIC (3 equivalents)in DMF. The final concentration was 0.2-0.3M. The reaction mixture wasleft overnight at room temperature.

The polymer was washed 6 times with DMF. The Fmoc protective group waseliminated with 50% piperidine in DMF (5+15 minutes).

Fmoc-isoserine (3 equivalents) was then coupled on with HOBt (3equivalents) and DIC (3 equivalents) in DMF (final concentration: about0.2M) over a period of at least 4 hours. The Fmoc protective group waseliminated with 50% piperidine in DMF (5+15 minutes). The polymer waswashed 5 times with DMF and 4 times with DCM and mixed with a solutionof 1.5 equivalents of 2-methoxy-5-chlorobenzenesulfonyl chloride and 3equivalents of DIEA in DCM (final concentration: 0.1-0.15M) and reactedat room temperature for 5 hours. It was then washed 5 times with DMF and5 times with DCM and dried in vacuo.

For the cyclative cleavage off, the dry polymer was mixed with 10 ml offormic acid and shaken at room temperature for 16 hours. The polymer wasfiltered off and washed with DCM. The combined filtrates were evaporatedin vacuo. The crude substance was dissolved in a mixture of acetonitrileand water and freeze dried. The pure title compound was removed afterpurification by HPLC. The system and processes described under “Generalprocesses” were used in this case. MW=555.10 (calculated, monoisotopic);measured value (M+H)⁺: 556.3

EXAMPLE 75-(4-Chlorobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-7-isopropyltetrahydroimidazo[1,2-a]pyrazine-3,6-dione

Structure:

0.3 g of TentaGel HL12019 (bromoacetal linker, S=0.5 mmol/g, RappPolymere, Tuibingen) was washed with DMSO. 20 equivalents of 2Misopropylamine solution in DMSO were added, and the mixture was kept ina closed vessel at 60° C. for 15 hours. The polymer was washed 7 timeswith DMF.

Fmoc-4-chlorophenylalanine (3 equivalents) was coupled to the secondaryamine on the polymer with HOAt (3 equivalents) and DIC (3 equivalents)in DMF. The final concentration was 0.2-0.3M. The reaction mixture wasleft overnight at room temperature. The polymer was washed 6 times withDMF. The Fmoc protective group was eliminated with 50% piperidine in DMF(5+15 minutes).

Fmoc-glycine (3 equivalents) was then coupled on with HOBt (3equivalents) and DIC (3 equivalents) in DMF (final concentration: about0.2M) over a period of at least 4 hours. The Fmoc protective group waseliminated with 50% piperidine in DMF (5+15 minutes). The polymer waswashed 5 times with DMF and 4 times with acetonitrile and mixed with asolution of 1.5 equivalents of 2-methoxy-4-chlorobenzenesulfonylchloride and 3 equivalents of DIEA in acetonitrile (final concentration:0.1-0.15M) and reacted at room temperature for 5 hours. It was thenwashed 5 times with DMF and 5 times with DCM and dried in vacuo.

For the cyclative cleavage off, the dry polymer was mixed with 10 ml offormic acid and shaken at room temperature for 24 hours. The polymer wasfiltered off and washed with DCM. The combined filtrates were evaporatedin vacuo. The crude substance was dissolved in a mixture of acetonitrileand water and freeze dried. The pure title compound was removed afterpurification by HPLC. The system and processes described under

“General processes” were used in this case. MW=525.09 (calculated,monoisotopic); measured value (M+H)⁺: 526.3.

EXAMPLE 85-(4-Chlorobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-7-Isopropyl-2-methyltetrahydroimidazo[1,2-a]pyrazine-3,6-dione

Structure:

0.3 g of TentaGel HL12019 (bromoacetal linker, S=0.5 mmol/g, RappPolymere, Tuibingen) was washed with DMSO. 20 equivalents of 2Misopropylamine solution in DMSO were added, and the mixture was kept ina closed vessel at 60° C. for 15 hours. The polymer was washed 7 timeswith DMF.

Fmoc-4-chlorophenylalanine (3 equivalents) was coupled to the secondaryamine on the polymer with HOAt (3 equivalents) and DIC (3 equivalents)in DMF. The final concentration was 0.2-0.3M. The reaction mixture wasleft overnight at room temperature. The polymer was washed 6 times withDMF. The Fmoc protective group was eliminated with 50% piperidine in DMF(5+15 minutes).

Fmoc-(R)-alanine (3 equivalents) was then coupled on with HOBt (3equivalents) and DIC (3 equivalents) in DMF (final concentration: about0.2M) over a period of at least 4 hours. The Fmoc protective group waseliminated with 50% piperidine in DMF (5+15 minutes). The polymer waswashed 5 times with DMF and 4 times with acetonitrile and mixed with asolution of 1.5 equivalents of 2-methoxy-4-chlorobenzenesulfonylchloride and

3 equivalents of DIEA in acetonitrile (final concentration: 0.1-0.15M)and reacted at room temperature for 5 hours. It was then washed 5 timeswith DMF and 5 times with DCM and dried in vacuo.

For the cyclative cleavage off, the dry polymer was mixed with 10 ml offormic acid and shaken at room temperature for 24 hours. The polymer wasfiltered off and washed with DCM. The combined filtrates were evaporatedin vacuo. The crude substance was dissolved in a mixture of acetonitrileand water and freeze dried. The pure title compound was removed afterpurification by HPLC. The system and processes described under “Generalprocesses” were used in this case. MW=539.10 (calculated, monoisotopic);measured value (M+H)⁺: 540.3.

EXAMPLE 91-(5-Chloro-2-methoxybenzenesulfonyl)-6-cyclohexylmethyl-8-Isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 9 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-cyclohexylalanine-   Reagent 3: 2-methoxy-5-chlorobenzenesulfonyl chloride-   MW=511.19 (calculated, monoisotopic); measured value (M+H)⁺: 512.3.

EXAMPLE 101-(5-Chloro-2-methoxybenzenesulfonyl)-6-Cyclohexyl-8-Isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 10 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-cyclohexylglycine-   Reagent 3: 2-methoxy-5-chlorobenzenesulfonyl chloride-   MW=497.18 (calculated, monoisotopic); measured value (M+H)⁺:498.3.

EXAMPLE 111-(5-Chloro-2-methoxybenzenesulfonyl)-8-Isopropyl-6-Phenethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 11 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-homophenylalanine-   Reagent 3: 2-methoxy-5-chlorobenzenesulfonyl chloride-   MW=519.18 (calculated, monoisotopic); measured value (M+H)⁺: 520.3.

EXAMPLE 121-(5-Chloro-2-methoxybenzenesulfonyl)-6-indan-1-yl-8-Isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 12 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-indanylglycine-   Reagent 3: 2-methoxy-5-chlorobenzenesulfonyl chloride-   MW=531.16 (calculated, monoisotopic); measured value (M+H)⁺: 532.3.

EXAMPLE 131-(5-Chloro-2-methoxybenzenesulfonyl)-6-[2-(4-Hydroxyphenyl)ethyl]-8-Isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 13 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-homotyrosine-   Reagent 3: 2-methoxy-5-chlorobenzenesulfonyl chloride-   MW=535.15 (calculated, monoisotopic); measured value (M+H)⁺: 536.3.

EXAMPLE 148-Isopropyl-6-(4-methoxybenzyl)-1-(2-methoxy-5-methylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 14 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-O-methyltyrosine-   Reagent 3: 2-methoxy-5-methylbenzenesulfonyl chloride-   MW=515.21 (calculated, monoisotopic); measured value (M+H)⁺: 516.3.

EXAMPLE 156-(4-Fluorobenzyl)-8-isopropyl-1-(2-methoxy-5-methylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 15 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-fluorophenylalanine-   Reagent 3: 2-methoxy-5-methylbenzenesulfonyl chloride-   MW=503.19 (calculated, monoisotopic); measured value (M+H)⁺: 504.3.

EXAMPLE 168-Isopropyl-1-(2-methoxy-5-methylbenzenesulfonyl)-6-(4-methylbenzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 16 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-methylphenylalanine-   Reagent 3: 2-methoxy-5-methylbenzenesulfonyl chloride-   MW=499.21 (calculated, monoisotopic); measured value (M+H)⁺: 500.3.

EXAMPLE 176-(4-Bromobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 17 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-bromophenylalanine-   Reagent 3: 2-methoxy-5-methylbenzenesulfonyl chloride-   MW=583.05 (calculated, monoisotopic); measured value (M+H)⁺: 584.3.

EXAMPLE 181-(5-Chloro-2-methoxybenzenesulfonyl)-6-(4-fluorobenzyl)-8-isopropylhexahydropyrazino[1 ,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 18 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-fluorophenylalanine-   Reagent 3: 2-methoxy-5-chlorobenzenesulfonyl chloride-   MW=523.13 (calculated, monoisotopic); measured value (M+H)⁺: 524.3.

EXAMPLE 191-(5-Chloro-2-methoxybenzenesulfonyl)-8-isopropyl-6-(4-methylbenzyl)hexahydropyrazino[1 ,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 19 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-methylphenylalanine-   Reagent 3: 2-methoxy-5-chlorobenzenesulfonyl chloride-   MW=519.16 (calculated, monoisotopic); measured value (M+H)⁺: 520.3.

EXAMPLE 201-(4-Bromo-2-ethylbenzenesulfonyl)-8-isopropyl-6-(4-methoxybenzyl)hexahydropyrazino[1 ,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 20 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-O-methyltyrosine-   Reagent 3: 2-ethyl-4-bromobenzenesulfonyl chloride-   MW=577.12 (calculated, monoisotopic); measured value (M+H)⁺: 578.3.

EXAMPLE 216-(4-Bromobenzyl)-1-(4-bromo-2-ethylbenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 21 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-bromophenylalanine-   Reagent 3: 2-ethyl-4-bromobenzenesulfonyl chloride-   MW=625.02 (calculated, monoisotopic); measured value (M+H)⁺: 626.4.

EXAMPLE 221-(4-Bromo-2-ethylbenzenesulfonyl)-6-(4-fluorobenzyl)-8-isopropylhexahydropyrazino[1 ,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 22 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-fluorophenylalanine-   Reagent 3: 2-ethyl-4-bromobenzenesulfonyl chloride-   MW=565.10 (calculated, monoisotopic); measured value (M+H)⁺: 566.3.

EXAMPLE 231-(4-Bromo-2-ethylbenzenesulfonyl)-8-isopropyl-6-(4-methylbenzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 23 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-methylphenylalanine-   Reagent 3: 2-ethyl-4-bromobenzenesulfonyl chloride-   MW=561.13 (calculated, monoisotopic); measured value (M+H)⁺: 562.3.

EXAMPLE 248-Isopropyl-6-(4-methoxybenzyl)-1-(3-trifluoromethylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 24 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-O-methyltyrosine-   Reagent 3: 3-trifluoromethylbenzenesulfonyl chloride-   MW=539.17 (calculated, monoisotopic); measured value (M+H)⁺: 540.3.

EXAMPLE 256-(4-Bromobenzyl)-8-isopropyl-1-(3-trifluoromethylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 25 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-bromophenylalanine-   Reagent 3: 3-trifluoromethylbenzenesulfonyl chloride-   MW=587.07 (calculated, monoisotopic); measured value (M+H)⁺: 588.3.

EXAMPLE 266-(4-Fluorobenzyl)-8-isopropyl-1-(3-trifluoromethylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 26 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-fluorophenylalanine-   Reagent 3: 3-trifluoromethylbenzenesulfonyl chloride-   MW=527.15 (calculated, monoisotopic); measured value (M+H)⁺: 528.3.

EXAMPLE 278-Isopropyl-6-(4-methylbenzyl)-1-(3-trifluoromethylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 27 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-methylphenylalanine-   Reagent 3: 3-trifluoromethylbenzenesulfonyl chloride-   MW=523.18 (calculated, monoisotopic); measured value (M+H)⁺: 524.3.

EXAMPLE 281-(2,5-Dimethylbenzenesulfonyl)-8-isopropyl-6-(4-methoxybenzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 28 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-O-methyltyrosine-   Reagent 3: 2,5-dimethylbenzenesulfonyl chloride-   MW=499.21 (calculated, monoisotopic); measured value (M+H)⁺: 500.3.

EXAMPLE 296-(4-Bromobenzyl)-1-(2,5-dimethylbenzenesulfonyl)-8-isopropylhexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 29 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-bromophenylalanine-   Reagent 3: 2,5-dimethylbenzenesulfonyl chloride-   MW=547.11 (calculated, monoisotopic); measured value (M+H)⁺: 548.3.

EXAMPLE 301-(2,5-Dimethylbenzenesulfonyl)-6-(4-fluorobenzyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 30 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-fluorophenylalanine-   Reagent 3: 2,5-dimethylbenzenesulfonyl chloride-   MW=487.19 (calculated, monoisotopic); measured value (M+H)⁺: 488.3.

EXAMPLE 311-(2,5-Dimethylbenzenesulfonyl)-8-isopropyl-6-(4-methylbenzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 31 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-methylphenylalanine-   Reagent 3: 2,5-dimethyl benzenesulfonyl chloride-   MW=483.22 (calculated, monoisotopic); measured value (M+H)⁺: 484.3.

EXAMPLE 326-(4-Chlorobenzyl)-1-(4-chloro-2,5-dimethylbenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 32 was synthesized by the process described inExample 1 using the following reagents:

-   Reagent 1: isopropyl amine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 4-Chloro-2,5-dimethylbenzenesulfonyl chloride-   MW=537.13 (calculated, monoisotopic); measured value (M+H)⁺: 538.3.

EXAMPLE 336-(4-Chlorobenzyl)-8-isopropyl-1-(2-nitrobenzenesulfonyl)hexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 33 was synthesized by the process described inExample 1 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-nitrobenzenesulfonyl chloride-   MW=520.12 (calculated, monoisotopic); measured value (M+H)⁺: 521.3.

EXAMPLE 346-(4-Chlorobenzyl)-1-(2,4-dichloro-5-methylbenzenesulfonyl)-8-Isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 34 was synthesized by the process described inExample 1 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2,4-dichloro-5-methylbenzenesulfonyl chloride-   MW=557.07 (calculated, monoisotopic); measured value (M+H)⁺: 558.3.

EXAMPLE 356-(4-Chlorobenzyl)-1-(2-chloro-4-trifluoromethylbenzenesulfonyl)-8-Isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 35 was synthesized by the process described inExample 1 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-chloro-4-trifluoromethylbenzenesulfonyl chloride-   MW=557.08 (calculated, monoisotopic); measured value (M+H)⁺: 578.3.

EXAMPLE 366-(4-Chlorobenzyl)-8-Isopropyl-1-(2-methyl-5-Nitrobenzenesulfonyl)hexahydropyrazino[1 ,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 36 was synthesized by the process described inExample 1 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-methyl-5-nitrobenzenesulfonyl chloride-   MW=534.13 (calculated, monoisotopic); measured value (M+H)⁺: 535.3.

EXAMPLE 371-(4-Bromo-2-Trifluoromethoxybenzenesulfonyl)-6-(4-Chlorobenzyl)-8-Isopropyl-hexahydropyrazino[1 ,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 37 was synthesized by the process described inExample 1 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 4-bromobenzene-2-trifluoromethoxysulfonyl chloride-   MW=637.03 (calculated, monoisotopic); measured value (M+H)⁺: 638.4.

EXAMPLE 386-(1-Benzyl-1H-imidazol-4-ylmethyl)-1-(4-Bromo-2-Ethylbenzenesulfonyl)-8-(2-pyridin-4-ylethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 38 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: 2-(4-pyridyl)ethylamine-   Reagent 2: Fmoc-histidine(benzyl)-   Reagent 3: 4-bromo-2-ethylbenzenesulfonyl chloride-   MW=690.16 (calculated, monoisotopic); measured value (M+H)⁺:691.4.

EXAMPLE 391-(5-Chloro-2-methoxybenzenesulfonyl)-8-isopropyl-6-(4-Nitrobenzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 39 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-nitrophenylalanine-   Reagent 3: 2-methoxy-5-chlorobenzenesulfonyl chloride-   MW=550.13 (calculated, monoisotopic); measured value (M+H)⁺: 551.3.

EXAMPLE 406-(4-Chlorobenzyl)-8-isopropyl-1-(naphthalene-2-Sulfonyl)hexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 40 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-naphthylsulfonyl chloride-   MW=525.15 (calculated, monoisotopic); measured value (M+H)⁺: 526.3.

EXAMPLE 41 6-(3,4-Dichlorobenzyl)-8-isopropyl-1-(naphthalene-2-Sulfonyl)hexahydropyrazino[1,2-a]-pyrimidine-4,7-dione

Structure:

The compound in Example 41 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-3,4-dichlorophenylalanine-   Reagent 3: 2-naphthylsulfonyl chloride-   MW=559.11 (calculated, monoisotopic); measured value (M+H)⁺: 560.3.

EXAMPLE 42

6-(3,4-Dichlorobenzyl)-1-(3,4-Dimethoxybenzenesulfonyl)-8-Isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 42 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-3,4-dichlorophenylalanine-   Reagent 3: 3,4-dimethoxybenzenesulfonyl chloride-   MW=569.12 (calculated, monoisotopic); measured value (M+H)⁺: 570.3.

EXAMPLE 438-Allyl-1-(4-bromo-2-ethylbenzenesulfonyl)-6-(4-Chlorobenzyl)hexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 43 was synthesized by the process described inEXAMPLE 2 using the following reagents:

-   Reagent 1: allylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-ethyl-4-bromobenzenesulfonyl chloride-   MW=579.06 (calculated, monoisotopic); measured value (M+H)⁺: 580.3.

EXAMPLE 448-Allyl-1-(4-bromo-2-ethylbenzenesulfonyl)-6-(4-Nitrobenzyl)hexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 44 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: allylamine-   Reagent 2: Fmoc-4-nitrophenylalanine-   Reagent 3: 2-ethyl-4-bromobenzenesulfonyl chloride-   MW=590.08 (calculated, monoisotopic); measured value (M+H)⁺: 591.3.

EXAMPLE 458-Allyl-1-(5-chloro-2-methoxybenzenesulfonyl)-6-(3,4-dichlorobenzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 45 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: allylamine-   Reagent 2: Fmoc-3,4-dichlorophenylalanine-   Reagent 3: 5-chloro-2-methoxybenzenesulfonyl chloride-   MW=571.05 (calculated, monoisotopic); measured value (M+H)⁺: 572.3.

EXAMPLE 468-Allyl-1-(naphthalene-2-sulfonyl)-6-(4-nitrobenzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 46 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: allylamine-   Reagent 2: Fmoc-4-nitrophenylalanine-   Reagent 3: 2-naphthylsulfonyl chloride-   MW=534.16 (calculated, monoisotopic); measured value (M+H)⁺: 535.3.

EXAMPLE 471-(5-Chloro-2-methoxybenzenesulfonyl)-8-isopropyl-6-pyridin-4-ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 47 was synthesized by the process described inExample 1 using the following reagents:

-   Reagent 1: isopropylaamine-   Reagent 2: Fmoc-4-pyridylalanine-   Reagent 3: 2-methoxy-5-chlorobenzenesulfonyl chloride-   MW=506.14 (calculated, monoisotopic); measured value (M+H)⁺: 507.3.

EXAMPLE 481-(5-Bromo-2-methoxybenzenesulfonyl)-6-(4-chlorobenzyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 48 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 5-bromo-2-methoxybenzenesulfonyl chloride-   MW=583.05 (calculated, monoisotopic); measured value (M+H)⁺: 584.3.

EXAMPLE 496-(4-Chlorobenzyl)-8-isopropyl-1-(2-methoxy-5-methylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 49 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-methoxy-5-methylbenzenesulfonyl chloride-   MW=519.16 (calculated, monoisotopic); measured value (M+H)⁺: 520.3.

EXAMPLE 506-(4-Chlorobenzyl)-8-isopropyl-1-(2-trifluoromethoxybenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 50 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-trifluoromethoxybenzenesulfonyl chloride-   MW=559.12 (calculated, monoisotopic); measured value (M+H)⁺: 560.3.

EXAMPLE 516-(4-Chlorobenzyl)-8-isopropyl-1-(2-methanesulfonylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 51 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylaamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-methylsulfonylbenzenesulfonyl chloride-   MW=553.11 (calculated, monoisotopic); measured value (M+H)⁺: 554.3.

EXAMPLE 523-[6-(4-Chlorobenzyl)-8-isopropyl-4,7-dioxohexahydropyrazino[1,2-a]pyrimidine-1-sulfonyl]benzonitrile

Structure:

The compound in Example 52 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 3-cyanobenzenesulfonyl chloride-   MW=500.13 (calculated, monoisotopic); measured value (M+H)⁺: 501.3.

EXAMPLE 536-(4-Chlorobenzyl)-8-isopropyl-1-(3-trifluoromethylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 53 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 3-trifluoromethylbenzenesulfonyl chloride-   MW=543.12 (calculated, monoisotopic); measured value (M+H)⁺: 544.3.

EXAMPLE 546-(4-Chlorobenzyl)-8-isopropyl-1-(2,4,6-trichlorobenzenesulfonyl)hexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 54 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2,4,6-trichlorobenzenesulfonyl chloride-   MW=577.02 (calculated, monoisotopic); measured value (M+H)⁺: 578.3.

EXAMPLE 55 6-(4-Chlorobenzyl)-1-(2,5-dimethoxybenzenesulfonyl)-8-isopropylhexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 55 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2,5-dimethoxybenzenesulfonyl chloride-   MW=535.15 (calculated, monoisotopic); measured value (M+H)⁺: 536.3.

EXAMPLE 566-(4-Chlorobenzyl)-1-(2,5-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 56 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2,5-dichlorobenzenesulfonyl chloride-   MW=543.06 (calculated, monoisotopic); measured value (M+H)⁺: 544.3.

EXAMPLE 57 Allyl6-(4-chlorobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-8-isopropyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidine-2-carboxylate

Structure:

The compound in Example 57 was synthesized by the process described inExample 1 using the reagents listed below and with the followingmodifications:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   After this step and after elimination of the Fmoc protection, the    coupling of Fmoc-beta-alanine from the process in Example 1 was    replaced by a Pmoc-Asp(OH)-O-allyl coupling under the same    conditions. After elimination of the Fmoc protection, the synthesis    was continued in accordance with the process for Example 1 with    reagent 3.-   Reagent 3: 5-chloro-2-methoxybenzenesulfonyl chloride-   MW=623.13 (calculated, monoisotopic); measured value (M+H)⁺:624.4.

EXAMPLE 581-(5-Chloro-2-methoxybenzenesulfonyl)-8-isopropyl-6-(4-methoxybenzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 58 was synthesized by the process described inExample 1 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-O-methyltyrosine-   Reagent 3: 5-chloro-2-methoxybenzenesulfonyl chloride-   MW=535.15 (calculated, monoisotopic); measured value (M+H)⁺: 536.3.

EXAMPLE 592-(4-Aminobutyl)-6-(4-chlorobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 59 was synthesized by the process described inExample 1 using the reagents listed below and with the followingmodifications:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   After this step and after elimination of the Fmoc protection, the    coupling of Fmoc-beta-alanine from the process in Example 1 was    replaced by a Fmoc-beta-homolysine(Boc) coupling under the same    conditions. After elimination of the Fmoc protection, the synthesis    was continued in accordance with the process for Example 1 with    reagent 3.-   Reagent 3: 5-chloro-2-methoxybenzenesulfonyl chloride-   MW=610.18 (calculated, monoisotopic); measured value (M+H)⁺: 611.4.

EXAMPLE 606-(4-Chlorobenzyl)-8-ethyl-1-(2-methoxy-5-methylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 60 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: ethylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-methoxy-5-methylbenzenesulfonyl chloride-   MW=505.14 (calculated, monoisotopic); measured value (M+H)⁺: 506.3.

EXAMPLE 616-(4-Chlorobenzyl)-1-(2-methoxy-5-methylbenzenesulfonyl)-8-methylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 61 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: methylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-methoxy-5-methylbenzenesulfonyl chloride-   MW=491.13 (calculated, monoisotopic); measured value (M+H)⁺: 492.3.

EXAMPLE 626-(4-Chlorobenzyl)-8-isobutyl-1-(2-methoxy-5-methylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 62 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isobutylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-methoxy-5-methylbenzenesulfonyl chloride-   MW=533.18 (calculated, monoisotopic); measured value (M+H)⁺: 534.3.

EXAMPLE 636-(4-Chlorobenzyl)-8-isobutyl-1-(2-methoxy-5-methylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 63 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: 2-butylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-methoxy-5-methylbenzenesulfonyl chloride-   MW=533.18 (calculated, monoisotopic); measured value (M+H)⁺: 534.3.

EXAMPLE 641-(5-Chloro-2-methoxybenzenesulfonyl)-8-isopropyl-6-pyridin-3-ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 64 was synthesized by the process described inExample 1 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-3-pyridylalanine-   Reagent 3: 5-chloro-2-methoxybenzenesulfonyl chloride-   MW=506.14 (calculated, monoisotopic); measured value (M+H)⁺: 507.3.

EXAMPLE 656-(4-Chlorobenzyl)-8-cyclopropyl-1-(2-methoxy-5-methylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 65 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: cyclopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-methoxy-5-methylbenzenesulfonyl chloride-   MW=517.14 (calculated, monoisotopic); measured value (M+H)⁺: 518.3.

EXAMPLE 666-(4-Chlorobenzyl)-8-cyclopentyl-1-(2-methoxy-5-methylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dioneStructure:

The compound in Example 66 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: cyclopentylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-methoxy-5-methylbenzenesulfonyl chloride-   MW=545.18 (calculated, monoisotopic); measured value (M+H)⁺: 546.3.

EXAMPLE 676-(4-Chlorobenzyl)-1-(2-methoxy-5-methylbenzenesulfonyl)-8-propylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 67 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: n-propylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-methoxy-5-methylbenzenesulfonyl chloride-   MW=519.16 (calculated, monoisotopic); measured value (M+H)⁺: 520.3.

EXAMPLE 688-Allyl-6-(4-chlorobenzyl)-1-(2-methoxy-5-methylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 68 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: allylaamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-methoxy-5-methylbenzenesulfonyl chloride-   MW=517.14 (calculated, monoisotopic); measured value (M+H)⁺: 518.2.

EXAMPLE 691-(5-Bromo-2-methoxybenzenesulfonyl)-6-(4-chlorobenzyl)-8-ethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 69 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: ethylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-methoxy-5-bromobenzenesulfonyl chloride-   MW=569.04 (calculated, monoisotopic); measured value (M+H)⁺: 570.3.

EXAMPLE 706-(4-Chlorobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-8-ethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 70 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: ethylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-methoxy-5-chlorobenzenesulfonyl chloride-   MW=525.09 (calculated, monoisotopic); measured value (M+H)⁺: 526.3.

EXAMPLE 711-(4-Bromo-2-ethylbenzenesulfonyl)-6-(4-chlorobenzyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 71 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 5-bromo-2-ethylbenzenesulfonyl chloride-   MW=581.08 (calculated, monoisotopic); measured value (M+H)⁺: 582.3.

EXAMPLE 726-(4-Chlorobenzyl)-1-(2,5-dimethylbenzenesulfonyl)-8-ethylhexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 72 was synthesized by the process described inExample 2 using the following reagents:

-   Reagent 1: ethylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2,5-dimethylbenzenesulfonyl chloride-   MW=489.15 (calculated, monoisotopic); measured value (M+H)⁺: 490.3.

EXAMPLE 732-Chloro-5-[6-(4-chlorobenzyl)-8-isopropyl-4,7-dioxohexahydropyrazino[1,2-a]-pyrimidine-1-sulfonyl]benzenesulfonamide

Structure:

The compound in Example 73 was synthesized by the process described inExample 1 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 4-chloro-2-sulfonylamidobenzenesulfonyl chloride-   MW=588.07 (calculated, monoisotopic); measured value (M+H)⁺: 589.3.

EXAMPLE 746-(4-Chlorobenzyl)-1-(2,4-dichloro-6-methylbenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 74 was synthesized by the process described inExample 1 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-methyl-4,6-dichlorobenzenesulfonyl chloride-   MW=557.08 (calculated, monoisotopic); measured value (M+H)⁺: 558.3.

EXAMPLE 756-(4-Chlorobenzyl)-8-isopropyl-1-(2-methoxy-4-methylbenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

The compound in Example 75 was synthesized by the process described inExample 1 using the following reagents:

-   Reagent 1: isopropylamine-   Reagent 2: Fmoc-4-chlorophenylalanine-   Reagent 3: 2-methoxy-4-methylbenzenesulfonyl chloride-   MW=519.16 (calculated, monoisotopic); measured value (M+H)⁺: 520.3.

EXAMPLE 766-(4-Chlorobenzyl)-8-isopropyl-1-(4-methoxybenzenesulfonyl)hexahydropyrazino[1,2-a]-pyrimidine-4,7-dione

Structure:

a)3-(4-Chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(4-methoxybenzenesulfonylamino)propionylamino]propionamide

52 mg of EDC, 45 mg of HOBt and 100 μl of N-ethylmorpholine are added toa solution of 124 mg of 3-(4-methoxybenzenesulfonylamino)propionic acidin 1 ml of DMF. A solution of 100 mg of2-amino-3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamidein 1 ml of DMF is added dropwise thereto, and the mixture is left tostir for 12 h. The reaction solution is filtered, mixed with ethylacetate and then extracted with 5% aqueous sodium bicarbonate solutionand aqueous sodium chloride solution. Drying of the organic phase withChromabond XTR is followed by concentration under reduced pressure, andthe residue is separated by HPLC (Knauer Eurospher-100-10-C18, water(0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroaceticacid)=80/20-10/90). The desired product is obtained with MW=598.16(calculated); measured value (M-C₂H₆O+H)⁺: 552.1

b)6-(4-Chlorobenzyl)-8-isopropyl-1-(4-methoxybenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

A solution of 167 mg of3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(4-methoxybenzenesulfonylamino)propionylamino]propionamidein 3 ml of formic acid is stirred at room temperature for 12 h. Thereaction solution is concentrated under reduced pressure, and theresidue is separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1%trifluoroacetic acid)/acetonitrile (0.1% trifluoroaceticacid)=80/20→10/90). The desired product is obtained with MW=506.02(calculated); measured value (M+H)⁺: 506.34

EXAMPLE 771-(4-Chlorobenzenesulfonyl)-6-(4-chlorobenzyl)-8-isopropylhexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

a)3-(4-Chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(4-chlorobenzenesulfonylamino)propionylamino]propionamide

Synthesis takes place in analogy to Example 76a) starting from3-(4-chlorobenzenesulfonylamino)propionic acid. The desired product isobtained with MW=602.58 (calculated); measured value (M-C₂H₆O+H)⁺: 556.1

b)6-(4-Chlorobenzyl)-8-isopropyl-1-(4-chlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Synthesis takes place in analogy to Example 76b) starting from3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(4-chlorobenzenesulfonylamino)propionylamino]-propionamide.The desired product is obtained with MW=510.44 (calculated); measuredvalue (M+H)⁺: 510.30

EXAMPLE 786-(4-Chlorobenzyl)-1-(3,4-dimethoxybenzenesulfonyl)-8-isopropylhexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

a) 3-(3,4-Dimethoxybenzenesulfonylamino)propionic acid

A solution of 3.8 g of 3,4-dimethoxybenzenesulfonyl chloride in 5 ml ofdioxane is added dropwise to a solution of 1.5 g of 3-aminopropionicacid in 20 ml of 1N NaOH solution. The mixture is left to stir whilecontrolling the pH (pH>7) for 12 h, the pH is reduced below 7 by addingcitric acid, and the reaction solution is then extracted with methylenechloride. The organic phase is dried over magnesium sulfate,concentrated under reduced pressure and employed without furtherpurification in the next reaction step. The desired product is obtainedwith MW=289.31 (calculated); measured value (M+H)⁺: 290.1

b)3-(3,4-Dimethoxyphenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(4-chlorobenzenesulfonylamino)propionylamino]propionamide

Synthesis takes place in analogy to Example 76a) starting from3-(3,4-dimethoxybenzenesulfonylamino)propionic acid. The desired productis obtained with MW=628.19 (calculated); measured value (M+H)⁺: 582.3

c)6-(4-Chlorobenzyl)-1-(3,4-dimethoxybenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Synthesis takes place in analogy to Example 76b) starting from3-(3,4-dimethoxyphenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(4-chlorobenzenesulfonylamino)propionylamino]-propionamide.The desired product is obtained with MW=536.05 (calculated); measuredvalue (M+H)⁺: 536.36

EXAMPLE 791-(3-Chlorobenzenesulfonyl)-6-(4-chlorobenzyl)-8-isopropylhexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

a) 3-(2-Chlorobenzenesulfonylamino)propionic acid

Synthesis takes place in analogy to Example 78a) starting from2-chlorobenzenesulfonyl chloride. The desired product is obtained withMW=263.70 (calculated); measured value (M+H)⁺: 264.05

b)3-(4-Chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(2-chlorobenzenesulfonylamino)propionylamino]propionamide

Synthesis takes place in analogy to Example 76a) starting from3-(2-chlorobenzenesulfonylamino)propionic acid. The desired product isobtained with product with MW=602.58 (calculated); measured value(M-C₂H₆O+H)⁺: 556.7

c)1-(3-Chlorobenzenesulfonyl)-6-(4-chlorobenzyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Synthesis takes place in analogy to Example 76b) starting from3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(2-chlorobenzenesulfonylamino)propionylamino]propionamide.The desired product is obtained with MW=510.44 (calculated); measuredvalue (M+H)⁺: 510.10

EXAMPLE 806-(4-Chlorobenzyl)-1-(4-fluorobenzenesulfonyl)-8-isopropylhexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

a)3-(4-Chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(4-fluorobenzenesulfonylamino)propionylamino]propionamide

Synthesis takes place in analogy to Example 78) starting from3-(4-fluorobenzenesulfonylamino)propionic acid. The desired product isobtained with MW=586.13 (calculated); measured value (M-C₂H₆O+H)⁺: 540.7

b)6-(4-Chlorobenzyl)-8-isopropyl-1-(4-fluorobenzenesulfonyl)hexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Synthesis takes place in analogy to Example 76b) starting from3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(4-fluorobenzenesulfonylamino)-propionylamino]propionamide.The desired product is obtained with MW=493.99 (calculated); measuredvalue (M+H)⁺: 494.13

EXAMPLE 816-(4-Chlorobenzyl)-1-(2,5-dimethoxybenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

a) 3-(2,5-Dimethoxybenzenesulfonylamino)propionic acid

Synthesis takes place in analogy to Example 78a) starting from2,5-dimethoxybenzenesulfonyl chloride. The desired product is obtainedwith MW=289.31 (calculated); measured value (M+H)⁺: 290.1

b)3-(2,5-Dimethoxyphenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(4-chlorobenzenesulfonylamino)propionylamino]propionamide

Synthesis takes place in analogy to Example 76a) starting from3-(2,5-dimethoxybenzenesulfonylamino)propionic acid. The desired productis obtained with MW=628.19 (calculated); measured value (M-C₂H₆O+H)⁺:582.7

c)6-(4-Chlorobenzyl)-1-(2,5-dimethoxybenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Synthesis takes place in analogy to Example 76b) starting from3-(2,5-dimethoxyphenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(4-chlorobenzenesulfonylamino)propionylamino]-propionamide.The desired product is obtained with MW=536.05 (calculated); measuredvalue (M+H)⁺: 536.16

EXAMPLE 826-(4-Chlorobenzyl)-1-(3-fluorobenzenesulfonyl)-8-isopropylhexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

a) 3-(3-Fluorobenzenesulfonylamino)propionic acid

Synthesis takes place in analogy to Example 78a) starting from3-fluorobenzenesulfonyl chloride. The desired product is obtained withMW=247.25 (calculated); measured value (M+H)⁺: 248.05

b)3-(4-Chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(3-fluorobenzenesulfonylamino)propionylamino]propionamide

Synthesis takes place in analogy to Example 76a) starting from3-(3-fluorobenzenesulfonylamino)propionic acid. The desired product isobtained with MW=586.13 (calculated); measured value (M-C₂H₆O+H)⁺: 540.7

c)6-(4-Chlorobenzyl)-8-isopropyl-1-(3-fluorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Synthesis takes place in analogy to Example 76b) starting from3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(3-fluorobenzenesulfonylamino)propionylamino]-propionamide.The desired product is obtained with MW=493.99 (calculated); measuredvalue (M+H)⁺: 494.25

EXAMPLE 83

1-Benzenesulfonyl-6-(4-chlorobenzyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Structure:

a)3-(4-Chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(benzenesulfonylamino)propionylamino]propionamide

Synthesis takes place in analogy to Example 78a) starting from3-(benzenesulfonylamino)propionic acid. The desired product is obtainedwith MW=568.13 (calculated); measured value (M-C₂H₆O+H)⁺: 522.7

b)6-(4-Chlorobenzyl)-8-isopropyl-1-(benzenesulfonyl)hexahydropyrazino[1,2-a]-pyrimidine-4,7-dione

Synthesis takes place in analogy to Example 76b) starting from3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(benzenesulfonylamino)propionylamino]propionamide.The desired product is obtained with MW=475.99 (calculated); measuredvalue (M+H)⁺: 476.14

EXAMPLE 846-(4-Chlorobenzyl)-1-(2-fluorobenzenesulfonyl)-8-isopropylhexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

a) 3-(2-Fluorobenzenesulfonylamino)propionic acid

Synthesis takes place in analogy to Example 78a) starting from2-fluorobenzenesulfonyl chloride. The desired product is obtained withMW=247.25 (calculated); measured value (M+H)⁺: 248.05

b)3-(4-Chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(2-fluorobenzenesulfonylamino)propionylamino]propionamide

Synthesis takes place in analogy to Example 76a) starting from3-(2-fluorobenzenesulfonylamino)propionic acid. The desired product isobtained with MW=586.13 (calculated); measured value (M-C₂H₆O+H)⁺: 540.7

c)6-(4-Chlorobenzyl)-8-isopropyl-1-(2-fluorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Synthesis takes place in analogy to Example 76b) starting from3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(2-fluorobenzenesulfonylamino)propionylamino]-propionamide.The desired product is obtained with MW=493.99 (calculated); measuredvalue (M+H)⁺: 494.13

EXAMPLE 856-(4-Chlorobenzyl)-1-(2,4-difluorobenzenesulfonyl)-8-isopropylhexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

a) 3-(2,4-Difluorobenzenesulfonylamino)propionic acid

Synthesis takes place in analogy to Example 78a) starting from2,4-difluorobenzenesulfonyl chloride. The desired product is obtainedwith MW=265.25 (calculated); measured value (M+H)⁺: 266.05

b)3-(4-Chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(2,4-difluorobenzenesulfonylamino)propionylamino]propionamide

Synthesis takes place in analogy to Example 76a) starting from3-(2,4-difluorobenzenesulfonylamino)propionic acid. The desired productis obtained with MW=604.13 (calculated); measured value (M-C₂H₆O+H)⁺:558.7

c)6-(4-Chlorobenzyl)-8-isopropyl-1-(2,4-difluorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Synthesis takes place in analogy to Example 76b) starting from3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(2,4-difluorobenzenesulfonylamino)-propionylamino]propionamide.The desired product is obtained with MW=511.99 (calculated); measuredvalue (M+H)⁺: 512.12

EXAMPLE 866-(4-Chlorobenzyl)-1-(3,4-difluorobenzenesulfonyl)-8-isopropylhexahydropyrazino-[1,2-a]pyrimidine-4,7-dione

Structure:

a) 3-(3,4-Difluorobenzenesulfonylamino)propionic acid

Synthesis takes place in analogy to Example 78a) starting from3,4-difluorobenzenesulfonyl chloride. The desired product is obtainedwith MW=265.25 (calculated); measured value (M+H)⁺: 266.05

b)3-(4-Chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(3,4-difluorobenzenesulfonylamino)propionylamino]propionamide

Synthesis takes place in analogy to Example 76a) starting from3-(3,4-difluorobenzenesulfonylamino)propionic acid. The desired productis obtained with MW=604.13 (calculated); measured value (M+H)⁺: 558.7

c)6-(4-Chlorobenzyl)-8-isopropyl-1-(3,4-difluorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione

Synthesis takes place in analogy to Example 76b) starting from3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(3,4-difluorobenzenesulfonylamino)-propionylamino]propionamide. Thedesired product is obtained with MW=511.99 (calculated); measured value(M+H)⁺: 512.12

1. A compound of the formula I,

wherein A is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, and 12-memberedmono-, bi- or spirobicyclic ring containing one or more heteroatomsselected from the group of N, O and S, and is optionally substitutedwith F, Cl, Br, NO₂, CF₃, OCF₃, CN, (C₁-C₆)-alkyl, aryl, CON(R11)(R12),N(R13)(R14), OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, N(R15)CO(C₁-C₆)-alkylor COO—(C₁-C₆)-alkyl; R11, R12, R13, R14, R15 are each independently H,(C₁-C₆)-alkyl or a heterocycle; n is 0 or 1; m is 0, 1, 2, 3, 4, 5 or 6;R1 is R8, (C₁-C₆)-alkylene-R8, (C₂-C₆)-alkenylene-R9, (SO₂)-R8,(SO₂)-(C₁-C₆)-alkylene-R8, (SO₂)-(C₂-C₆)-alkenylene-R9, (C═O)-R8,(C═O)-(C₁-C₆)-alkylene-R8, (C═O)NH-R8, (C═O)-(C₂-C₆)-alkenylene-R9,(C═O)-NH-(C₁-C₆)-alkylene-R8, (C═O)-NH-(C₂-C₆)-alkenylene-R9, COO-R8,COO—(C₁-C₆)-alkylene-R8, COO—(C₂-C₆)-alkenylene-R9, alkynylene-R9 or(C₁-C₄-alkyl)-heterocycle, wherein the alkylene component of said(C₁-C₆)-alkylene-R8, (C₂-C₆)-alkenylene-R9, (SO₂)-(C₁-C₆)-alkylene-R8,(SO₂)-(C₂-C₆)-alkenylene-R9, (C═O)-(C₁-C₆)-alkylene-R8,(C═O)-(C₂-C₆)-alkenylene-R9, (C═O)-NH-(C₁-C₆)-alkylene-R8,(C═O)-NH-(C₂-C₆)-alkenylene-R9, COO—(C₁-C₆)-alkylene-R8,COO—(C₂-C₆)-alkenylene-R9 and alkynylene-R9 groups is optionallysubstituted by F; R8, R9 are each independently H, F, Cl, Br, I, OH,CF₃, aryl, heterocycle or (C₃-C₈)-cycloalkyl, wherein said aryl,heterocycle and (C₃-C₈)-cycloalkyl groups are optionally mono-, di- ortri-substituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, CON(R11)(R12), N(R13)(R14),SO₂-CH₃, COOH, COO—(C₁-C₆)-alkyl or CONH₂; R2 is H, F, Cl, Br, I, OH,CF₃, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl,(C₂-C₆)-alkynyl, aryl, O-aryl, (C₁-C₈)-alkylene-aryl,O—(C₁-C₈)-alkylene-aryl, S-aryl, CON(R11)(R12), N(R13)(R14),(C₁-C₆)-alkyl-N(R13)(R14), COOH, COO—(C₁-C₆)-alkyl, COO—(C₂-C₆)-alkenyl,CO-N((C₁-C₆)-alkyl)₂ or heterocycle, with the proviso that saidheterocycle may not be bonded via a nitrogen atom; R3, R4, R5 are eachindependently H, F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, aryl,O-aryl (C₁-C₈)-alkylene-aryl, O—(C₁-C₈)-alkylene-aryl, S-aryl,N((C₁-C₆)-alkyl)₂, SO₂-CH₃, COOH, COO—(C₁-C₆)-alkyl orCO-N((C₁-C₆)-alkyl)₂; R6 is H, F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl,(C₂-C₆)-alkynyl, (C₀-C₈)-alkylene-aryl, O—(C₀-C₈)-alkylene-aryl, S-aryl,N((C₁-C₆)-alkyl)₂, SO₂-CH₃, COOH, COO—(C₁-C₆)-alkyl orCO-N((C₁-C₆)-alkyl)₂; and pharmaceutically acceptable salts thereof. 2.The compound of claim 1 wherein A is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-,11-, and 12-membered mono-, bi- or spirobicyclic ring containing one ormore heteroatoms selected from the group of N, O and S, and isoptionally substituted with F, Cl, Br, NO₂, CF₃, OCF₃, CN,(C₁-C₆)-alkyl, aryl, CON(R11)(R12), N(R13)(R14), OH, O—(C₁-C₆)-alkyl,S—(C₁-C₆)-alkyl, N(R15)CO(C₁-C₆)-alkyl or COO—(C₁-C₆)-alkyl; R11, R12,R13, R14, R15 are each independently H, (C₁-C₆)-alkyl or a heterocycle;m is 1; n is 0 or 1; R1 is R8, (C₁-C₆)-alkylene-R8,(C₂-C₆)-alkenylene-R9, (SO₂)-R8, (SO₂)-(C₁-C₆)-alkylene-R8,(SO₂)-(C₂-C₆)-alkenylene-R9, (C═O)-R8, (C═O)-(C₁-C₆)-alkylene-R8,(C═O)NH-R8, (C═O)-(C₂-C₆)-alkenylene-R9, (C═O)-NH-(C₁-C₆)-alkylene-R8,(C═O)-NH-(C₂-C₆)-alkenylene-R9, COO-R8, COO—(C₁-C₆)-alkylene-R8,COO—(C₂-C₆)-alkenylene-R9, alkynylene-R9 or (C₁-C₄-alkyl)-heterocycle;R8, R9 are each independently H, F, Cl, Br, I, OH, CF₃, aryl,heterocycle or (C₃-C₈)-cycloalkyl, wherein said aryl, heterocycle and(C₃-C₈)-cycloalkyl groups are optionally mono-, di- or tri-substitutedby F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,NH₂, CON(R11)(R12), N(R13)(R14), SO₂-CH₃, COOH, COO—(C₁-C₆)-alkyl orCONH₂; R2 is H, F, Cl, Br, I, OH, CF₃, CN, OCF₃, O—(C₁-C₆)-alkyl,O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl, S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl, O—(C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl, (C₂-C₆)-alkynyl, aryl,O-aryl, (C₁-C₈)-alkylene-aryl, O—(C₁-C₈)-alkylene-aryl, S-aryl,CON(R11)(R12), N(R13)(R14), (C₁-C₆)-alkyl-N(R13)(R14), COOH,COO—(C₁-C₆)-alkyl, COO—(C₂-C₆)-alkenyl, CO-N((C₁-C₆)-alkyl)₂ orheterocycle, with the proviso that said heterocycle may not be bondedvia a nitrogen atom; R3, R4, R5 are each independently H, F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl,(C₂-C₆)-alkynyl, aryl, O-aryl (C₁-C₈)-alkylene-aryl,O—(C₁-C₈)-alkylene-aryl, S-aryl, N((C₁-C₆)-alkyl)₂, SO₂-CH₃, COOH,COO—(C₁-C₆)-alkyl or CO-N((C₁-C₆)-alkyl)₂; R6 is H, F, Cl, Br, I, OH,CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₁-C₄)-alkoxy-(C₁-C₄)-alkyl,S—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₃-C₈)-cycloalkyl,O—(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkenyl, O—(C₃-C₈)-cycloalkenyl,(C₂-C₆)-alkynyl, aryl, O-aryl, (C₁-C₈)-alkylene-aryl,O—(C₁-C₈)-alkylene-aryl, S-aryl, N((C₁-C₆)-alkYI)₂, SO₂-CH₃, COOH,COO—(C₁-C₆)-alkyl or CO-N((C₁-C₆)-alkyl)₂; and pharmaceuticallyacceptable salts thereof.
 3. The compound of claim 2 wherein A is arylwherein said aryl is optionally substituted by F, Cl, Br, NO₂, CF₃,OCF₃, CN, (C₁-C₆)-alkyl, aryl, CON(R11)(R12), N(R13)(R14), OH,O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl, N(R15)CO(C₁-C₆)-alkyl orCOO—(C₁-C₆)-alkyl; R11, R12, R13, R14, R15 are each independently H or(C₁-C₆)-alkyl; m is 1; R1 is (C₁-C₆)-alkylene-R8 or(C₂-C₆)-alkenylene-R9; R8, R9 are each independently H, F, Cl, Br, I,OH, CF₃, aryl, heterocycle or (C₃-C₈)-cycloalkyl, wherein said aryl,heterocycle and (C₃-C₈)-cycloalkyl groups are optionally mono-, di-, ortri-substituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, CON(R11)(R12), N(R13)(R14),SO₂-CH₃, COOH, COO—(C₁-C₆)-alkyl or CONH₂; R2 is H, F, Cl, Br, I, OH,CF₃, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, N(R13)(R14),(C₁-C₆)-alkyl-N(R13)(R14) or COO—(C₂-C₆)-alkenyl, R3 is H R4, R5 areeach independently H, F, Cl, Br, OH, CF₃, OCF₃, O—(C₁-C₆)-alkyl or(C₁-C₆)-alkyl; R6 is H; and pharmaceutically acceptable salts thereof.4. The compound of claim 3 wherein A is aryl wherein said aryl isoptionally substituted by F, Cl, Br, NO₂, CF₃, OCF₃, CN, (C₁-C₆)-alkyl,aryl, CON(R11)(R12), N(R13)(R14), OH, O—(C₁-C₆)-alkyl, S—(C₁-C₆)-alkyl,N(R15)CO(C₁-C₆)-alkyl or COO—(C₁-C₆)-alkyl; R11, R12, R13, R14, R15 areeach independently H or (C₁-C₆)-alkyl; m is 1; n is 0 or 1; R1 is(C₁-C₆)-alkyl or (C₂-C₆)-alkenyl; R2 is H, OH, (C₁-C₆)-alkyl,COO—(C₂-C₆)-alkenyl or (C₁-C₆)-alkyl-N(R13)(R14); R3 is H R4 is F, Cl,Br, OH, CF₃, OCF₃, O—(C₁-C₆)-alkyl or (C₁-C₆)-alkyl; R5 is H, F, Cl, Br,OH, CF₃, OCF₃, O—(C₁-C₆)-alkyl or (C₁-C₆)-alkyl; R6 is H; andpharmaceutically acceptable salts thereof.
 5. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 6. The pharmaceutical composition of claim 5 furthercomprising one or more anorectic active ingredients.
 7. Thepharmaceutical composition of claim 5 further comprising one or morestatins.
 8. The pharmaceutical composition of claim 5 further comprisingone or more antidiabetics, hypoglycemic active ingredients, HMGCoAreductase inhibitors, cholesterol absorption inhibitors, PPAR gammaagonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTPinhibitors, bile acid adsorption inhibitors, CETP inhibitors, polymericbile acid adsorbents, LDL receptor inducers, ACAT inhibitors,antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyaseinhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists,lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides,thiazolidinediones, α-glucosidase inhibitors, active ingredients actingon the ATP-dependent potassium channel of beta cells, CART agonists, NPYagonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRFagonists, CRF BP-antagonists, urocortin agonists, β3 agonists, MSH(melanocyte-stimulating hormone) agonists, CCK agonists, serotoninreuptake inhibitors, mixed sertoninergic and noradrenergic compounds,5HT agonists, bombesin agonists, galanin antagonists, growth hormones,growth hormone-releasing compounds, TRH agonists, uncoupling protein 2or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin),lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-βagonists or amphetamines.
 9. A method of treating obesity comprisingadministering to a patient in need thereof a compound of claim
 1. 10. Amethod of treating obesity comprising administering to a patient in needthereof a compound of claim 1 in combination with at least one furtheranorectic active ingredient.
 11. A method of treating type II diabetescomprising administering to a patient in need thereof a compound ofclaim
 1. 12. A method of treating type II diabetes comprisingadministering to a patient in need thereof a compound of claim 1 incombination with at least one further anorectic active ingredient.
 13. Amethod of reducing weight in mammals comprising administering to apatient in need thereof a compound of claim
 1. 14. A method of treatingmetabolic syndrome comprising administering to a patient in need thereofa compound of claim
 1. 15. A method of treating female and male sexualdisorders comprising administering to a patient in need thereof acompound of claim 1.